Each year, nearly 30 million general anesthetics are administered in the U.S. alone. At the concentrations required to produce anesthesia, all general anesthetics produce potentially serious and sometimes deadly side effects. Of particular concern is depression of cardiovascular and respiratory function, which can be life threatening, particularly in elderly, sick, and traumatized patients. These deleterious side effects are caused by nearly all general anesthetics and explain why anesthetics have among the lowest therapeutic indices (LD50/ED50) of any class of therapeutic drugs. Therefore, there is great value in developing safer anesthetic agents with fewer side effects.
Etomidate (ethyl 3-(1-phenylethyl)imidazole-4-carboxylate) is a rapidly acting imidazole-based I.V. sedative-hypnotic that can be used to induce and maintain general anesthesia or conscious sedation. It exists as two enantiomers; however, the (R)-enantiomer is ˜10-fold more potent an anesthetic than the (S)-enantiomer. The (R)-enantiomer is the one that is used clinically (see Structure 1, below). (R)-etomidate induces loss of righting reflexes in tadpoles (Husain, S. S., et al., J Med Chem, 46:1257-1265 (2003)) and loss of responsiveness in humans (Arden, J. R., et al., Anesthesiology, 65:19-27 (1986)) at a free-aqueous concentration of ˜2 μM.

At the molecular level, there is compelling evidence that etomidate produces anesthesia by enhancing the function of GABAA receptors containing β2 or β3 subunits. Etomidate enhances GABA receptor-mediated currents evoked by low concentrations of agonist, but minimally enhances currents evoked by high concentrations of agonist. This shifts the agonist concentration-response curve leftward (reduces the agonist EC50). Etomidate also directly activates GABAA receptors in the absence of agonist.
Compared to other general anesthetics, etomidate has an unusually high therapeutic index; (R)-etomidate's therapeutic index in animals is 26.4 compared to 4.6 and 3.1 for thiopental and propofol, respectively (Janssen, P. A., Arzneimittelforschung, 21:1234-1243 (1971), Glen, J. B., Br J Anaesth, 52:731-742 (1980), and Zhou, Anesth Analg, 102:129-134 (2006)). The relatively large safety margin afforded by etomidate presumably reflects its lesser effect on cardiovascular and respiratory function. The hemodynamic stability afforded by etomidate is due, at least in part, to its lack of depressant effect on sympathetic outflow and autonomic reflexes (Ebert, T. J., et al., Anesthesiology 76:725-733 (1992)). Conversely, propofol and thiopental reduce sympathetic outflow, blunt autonomic reflexes and directly impair myocardial contractility (Mazerolles, M., Fundam Clin Pharmacol, 10:298-303 (1996)). These actions produce cardiovascular depression even in healthy patients. Because of (R)-etomidate's lesser effects on cardiovascular and respiratory function, it has emerged as an anesthetic agent of choice by anesthesiologists, intensivists, and emergency room physicians for use in sick, elderly, or traumatized patients. However, this enthusiasm is tempered and its clinical use limited by its remarkably potent and prolonged inhibition of adrenocortical steroid synthesis.
Inhibition of steroid synthesis is a potentially deadly side effect of prolonged (R)-etomidate administration, particularly in those patients who would otherwise benefit most from its favorable cardiovascular and respiratory properties: the critically ill. This inhibition is extremely potent, occurring at (R)-etomidate concentrations far below those used to produce sedation or anesthesia. At the doses necessary to produce general anesthesia, (R)-etomidate causes adrenal insufficiency that can persist for more than 4 days after discontinuing a prolonged infusion (Wagner, R. L., and White, P. F., Anesthesiology, 61:647-651 (1984)), resulting in significantly increased mortality in critically ill patients (Watt, I., and Ledingham, I. M., Anaesthesia, 39:973-981 (1984) and Ledingham, I. M., and Watt, I., Lancet, 1:1270 (1983)). Apparently, mortality can be reduced by empirically administering exogenous steroids; however, this approach is suboptimal as the dosing, timing, and duration of steroid therapy in any given patient would be speculative. Furthermore, the administration of exogenous steroids itself can produce serious complications including impaired glucose homeostasis and wound healing, immunosuppression, and fluid retention. Because of (R)-etomidate's profound effect on adrenocortical function, a specific warning against its administration by prolonged infusion has been added to its package insert and the use of (R)-etomidate for prolonged sedation or anesthesia has been abandoned.
The clinical significance of adrenocortical suppression following a single I.V. bolus is controversial. See Morris, C., and McAllister, C., Anaesthesia, 60:737-740 (2005); Jackson, W. L., Jr., Chest, 127:1031-1038 (2005); Murray, H., and Marik, P. E., Chest, 127:707-709 (2005); Zed, P. J., et al., Chem., 8:347-350 (2006); and Bloomfield, R., and Noble, D. W., Crit Care, 10:161 (2006). It has historically been assumed that adrenal suppression following a single bolus is brief (<8 hrs) and clinically unimportant. However, this assumption is mainly based on small studies of patients undergoing elective surgery who were not critically ill. See Wagner, R. L., and White, P. F., Anesthesiology, 61:647-651 (1984); Wagner, R. L., et al., N Engl J Med, 310:1415-1421 (1984); Fragen, R. J., et al., Anesthesiology 61:652-656 (1984); and Duthie, D. J., et al., Br J Anaesth, 57:156-159 (1985). A number of recent studies and reports of critically ill patients indicate that adrenal suppression following even a single bolus induction dose of (R)-etomidate can last for 24 hours or longer and some suggest that it increases the risk of death, particularly in the setting of sepsis. See Absalom A., et al., Anaesthesia, 54:861-867 (1999); Malerba, G., et al., Intensive Care Med, 31:388-392 (2005); den Brinker, M., et al., Intensive Care Med (2007); den Brinker, M., et al., J Clin Endocrinol Metab, 90:5110-5117 (2005); Lundy, J. B., et al., J Intensive Care Med, 22:111-117 (2007); Lipiner-Friedman, D., et al., Crit Care Med, 35:1012-1018 (2007); Vinclair, M., et al., Intensive Care Med., (2007); and Cotton, B. A., et al., Arch Surg, 143:62-67 (2008).
(R)-etomidate inhibits adrenocortical steroid synthesis primarily by inhibiting 11β-hydroxylase, a critical enzyme in the synthetic pathway leading to cortisol, corticosterone, and aldosterone production (see de Jong, F. H., et al., J Clin Endocrinol Metab, 59:1143-1147 (1984)). (R)-etomidate's half-maximal inhibitory concentration (IC50) has been reported to be 0.5-30 nM (see Lamberts, S. W., et al., J Pharmacol Exp Ther, 240:259-264 (1987)), a concentration range that is orders of magnitude lower than its anesthetizing concentration. When (R)-etomidate's extremely high 11β-hydroxylase inhibitory potency is considered along with its lengthy (several hours) elimination half-life (see Van Hamme, M. J., et al., Anesthesiology, 49:274-277 (1978)), we suggest that a logical explanation emerges for the long duration of adrenocortical suppression following (R)-etomidate administration: After administering an anesthetic dose, many elimination half-lives must pass before (R)-etomidate's serum concentration is sufficiently reduced by metabolism so that 11β-hydroxylase activity is no longer inhibited. This led to the prediction that the duration of adrenocortical suppression might be reduced by designing analogues of (R)-etomidate that are rapidly metabolized. Such rapidly metabolized analogues might also be predicted to have ultra-short durations of anesthetic action. This is another highly desirable anesthetic property because it allows more precise titration of anesthetic depth during surgery and faster emergence from anesthesia at the end of surgery.
There is a great need for safer general anesthetics, particularly for use in the critically ill. (R)-etomidate possesses many properties that make it an ideal general anesthetic agent, but its ability to potently suppress adrenocortical steroid synthesis severely limits its clinical utility and safety.
As discussed above, there is a need in the art to develop analogues of (R)-etomidate that retain it's many beneficial properties (e.g. rapid onset of action, little effect on blood pressure, high therapeutic index), but do not cause potentially dangerous inhibition of adrenocortical function. Such analogues will permit anesthesia to be administered more safely to patients who are critically ill. This invention answers that need.